Citations

Abstract Background: In the treatment of ER+/HER2- metastatic breast cancer (MBC), randomized phase II/III trials testing selective estrogen receptor degraders (SERDs), proteolysis-targeting chimeras (PROTACs), complete estrogen receptor antagonists (CERANs) and selective ER modulators (SERMs) (mostly compared to fulvestrant) have demonstrated modest (1-2 months) improvements in progression-free survival (PFS), mainly limited to patients with ESR1-mutated MBC. In these studies, the median PFS (mPFS) ranges from 3 to 6 months, with shorter mPFS in patients with prior progression on CDK 4/6 inhibitor (CDK 4/6i). Here we report the final results of a randomized phase II study that compared Z-endoxifen (Endx) 80 mg/day with tamoxifen (Tam) 20 mg/day in postmenopausal women with estrogen receptor (ER)- positive/ HER2-negative MBC, and report outcomes according to ESR1, PIK3CA, PTEN and AKT alterations (Alliance A011203; NCT02311933). Methods: Postmenopausal women with unlimited prior endocrine regimens (including CDK 4/6i) and up to two chemotherapy regimens for MBC, with tumor biopsy confirmation of ER+ (>10% nuclear staining) and negative for HER2 amplification/overexpression were eligible. Prior adjuvant Tam was allowed if relapse was > 1 year following Tam completion. Patients randomized to Tam could cross over to Endx at progression. The primary end point was PFS analyzed by the interval censored data analytic approach. ctDNA was analyzed for ESR1 and PIK3CA/PTEN/AKT alterations using Guardant360 CDx 74-gene next-generation sequencing-based assay (Guardant Health). Results: Among 108 women who preregistered, 76 (Endx: 40; Tam: 36) were randomized and eligible. Patients were heavily pretreated; all patients had prior exposure to an aromatase inhibitor (AI), 50% had ≥ 2 AI based regimens in the metastatic setting and 50% in each arm had received fulvestrant. Approximately half on each arm received at least one chemotherapy regimen in the metastatic setting. Prior CDK 4/6i therapy was imbalanced (48% on Endx and 28% on Tam). Endx did not significantly prolong PFS compared to Tam (median PFS [mPFS] 4.3 vs 1.7 months; HR 0.72, p=0.168). Because arms were imbalanced according to prior CDK 4/6i exposure, we performed an unplanned analysis demonstrating that Endx improved PFS relative to Tam in CDK 4/6i-naïve patients (mPFS 8.3 vs 2.1 months; HR 0.39, p=0.0097) but not in patients treated with prior CDK 4/6i (mPFS 3.0 vs 1.5 months). In the subset of patients who consented for ctDNA testing (n=28), the mPFS for those with either an activating alteration in the PIK3CA/PTEN/AKT pathway or with an ESR1 mutation was similar as the overall trial. For the 24 patients who progressed on Tam and crossed-over to Endx, the median PFS was 3.5 months (range 1.5-15.0 months) with a 6-month clinical benefit rate of 33.3% (8/24; 90% CI: 17.8-52.1%). Conclusions: Endx did not meet the prespecified threshold for concluding that it significantly improved PFS relative to Tam in a cohort of heavily pretreated MBC. However, the observations of a > 6-month improvement in mPFS in CDK 4/6i-naïve patients, anti-tumor activity following crossover to Tam, and mPFS estimates similar to other novel endocrine agents in development all support the ongoing development of Endx. Support: U10CA180821, U10CA180882, U24CA196171, U10CA180820 (ECOG-ACRIN) and 5P50CA116201. Clinicaltrials.gov Id: NCT02311933. https://acknowledgments.alliancefound.org. Citation Format: M. P. Goetz, V. Suman, J. Reid, T. Dockter, C. Strand, W. F. Symmans, J. Hawse, A. Storniolo, J. Doroshow, J. M. Collins, H. Streicher, M. M. Ames, A. Tarnower, O. M. Hahn, J. N. Ingle, L. Carey, A. Partridge. Final results from the Randomized Phase II study of Z-Endoxifen and Tamoxifen in Endocrine Refractory, Estrogen Receptor Positive, HER2 negative Metastatic Breast Cancer (Alliance A011203) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-08-07.

A retrospective review of multidisciplinary velopharyngeal insufficiency (VPI) Clinic records from 2010 to 2024 was completed. Inclusion criteria for the review were diagnosis of childhood apraxia of speech (CAS) and documented evaluation for velopharyngeal dysfunction (VPD). Adequacy of velopharyngeal closure and perceptual judgment of resonance were identified as primary outcome measures. Surgical interventions and speech outcomes were also described. This review identified 74 children who were diagnosed with CAS and evaluated for VPD in the VPI Clinic. For the subset (n = 50) of children who had surgical intervention, speech therapy, and long-term follow-up, all had improved velopharyngeal closure and resonance.

Introduction Despite its demonstrated effectiveness at improving outcomes, pulmonary rehabilitation (PR) for chronic obstructive pulmonary disease (COPD) is underutilized. Sensor-generated data from wearable devices have the potential to mitigate this challenge by generating digital endpoints that provide insights into patient behaviors at home; however, there is no consensus on how to measure home-based PR (HBPR) outcomes with these tools. This review aims to describe (1) the most frequent digital endpoints used in HBPR studies and (2) the devices used to capture these endpoints, summarizing gaps in their applications to HBPR for COPD patients. Methods We completed a scoping review using the PRISMA checklist across databases (Web of Science, Scopus, and OVID) from January 1, 2005 to June 1, 2025. We included peer-reviewed articles on HBPR for COPD, excluding reviews, commentaries/editorials, poster abstracts, and conference proceedings. Eligible articles included cohort studies and clinical trials of adult patients (age ≥ 18 years) with COPD participating in HBPR that include one or more digital endpoints. Results Among eligible articles ( n = 218), 13 (6.0%) met inclusion criteria, the majority of which were published after 2020 (61.5%). Most studies enrolled fewer than 100 COPD patients (76.9%) for an average monitoring period of 12.5 weeks. Activity trackers were the most commonly used device (46.2%) to capture data. The most frequently used digital endpoints were step count (84.6%), time spent active (38.5%), and time spent sedentary (30.8%). Two study designs were used: randomized controlled trial (76.9%) and observational cohort. Study designs were heterogenous with more than one-third (38.5%) presenting a lack of statistically significant results. Discussion Although we identified analogous digital endpoints in some studies, dissimilar methods and study designs remain barriers to synthesizing results generated from HBPR programs for COPD. Wearable devices have the potential to build novel PR models, but more work is needed to translate real-world data into clinically meaningful measures. Future research should elucidate which participants would benefit most from and complete HBPR to build an evidence base for the validation of HBPR-relevant digital endpoints, particularly those derived from less common sources like cardiovascular and sleep measures.

619 Background: Well-differentiated G3 GEP-NETs are rare and heterogeneous diseases, limiting phase III trials and definition of clear standards of care. Building upon our preliminary cohort of 76 patients (pts), we present an updated and expanded retrospective analysis across three Mayo Clinic tertiary centers. Methods: We included pts with histologically confirmed well-differentiated G3 GEP-NETs diagnosed since 2017 (new WHO classification) from the three Mayo Clinic sites (Rochester, Phoenix, Jacksonville). Endpoints were ORR, DCR, PFS, and OS across treatment lines. PFS/OS were estimated by Kaplan-Meier. OS was defined from treatment start. Multivariate Cox regression was used to evaluate the association of clinic-pathologic features (age, sex, tumor functionality, Ki-67, primary tumor site, stage at diagnosis, presence of liver metastasis, number of metastatic sites at diagnosis) with OS (p<0.05). Results: 111 pts (median age 62 y, range 22–83). Primary sites were pancreas (58%), small bowel (19%), unknown (9%), and rectum (5%). Most tumors were G3 at diagnosis (88%); the remainder evolved from prior G1/G2. Ki-67 was 20–55% in 83% of cases. Most were nonfunctional (70%); functional subtypes included carcinoid (13%) and gastrinoma (8%). Median plasma 5-HIAA was 38.5 ng/ml (5–1394). Advanced disease was present in 85%. Common metastatic sites included liver (85%), lymph nodes (32%), bone (26%), peritoneum (10%), and lung (9%). Median number of metastatic sites was 1 (range 0–5). Median number of systemic treatment lines was 2 (range 0–8). The most frequent regimens and outcomes are shown in the Table. Insulin-secreting tumors (HR 2.16, 95% CI 1.33–25.73, p=0.019) and ≥2 metastatic sites (HR 2.13, 95% CI 1.05–4.31, p=0.035) were associated with inferior OS. Conclusions: This represents one of the largest real-world datasets of well-differentiated G3 GEP-NETs and provides a deeper evaluation of treatment strategies and prognostic factors. CAPTEM, SSAs, and PRRT with Lu-177 emerged as the most commonly used therapies, with PRRT showing the most favorable outcomes. Insulin secretion and higher metastatic burden were confirmed as adverse prognostic factors. CAPTEM SSAs PRRT Lu-177 Carboplatin plus etoposide FOLFOX Everolimus Sunitinib N of pts (%) 64 (58) 44 (40) 37 (33) 24 (19) 18 (13) 11 (10) 8 (7) Line of therapy (%) First 36 (56.3) 27 (61.4) 5 (13.5) 13 (59.2) 5 (7.2) 1 (9.0) 1 (12.5) Second 15 (23.4) 13 (29.5) 13 (35.2) 3 (13.6) 5 (35.7) 3 (27.3) 2 (37.5) Third or higher 13 (20.3) 4 (9.1) 19 (51.3) 6 (27.2) 8 (57.1) 7 (63.7) 5 (62.5) DCR (%) 60.9 56.8 75.0 52.2 71.4 45.5 37.5 ORR (%) 34.4 13.6 44.4 30.4 35.7 18.2 12.5 mPFS (95% CI) 8.0 (5.3-10.6) 6.2 (2.8-9.5) 11.2 (9.1-13.3) 7.3 (2.8-11.8) 4.4 (2.4-6.4) 3.9 (2.2-5.6) 3.9 (1.54-6.26) mOS (95% CI) 40.1 (23.0-57.2) 50 (22.6-77.4) 76.1 (16.3-135.8) 33.0 (21.0-45.0) 21.1 (15.0-27.2) NE NE

Abstract Purpose: Combined mTOR and MEK inhibition, critical components of the RAS effector pathway underlying the pathogenesis of neurofibromatosis type 1 (NF1)–related tumors, caused regression in a malignant peripheral nerve sheath tumor (MPNST) transgenic mouse model. The primary objective was to determine the clinical benefit rate in patients with unresectable/metastatic MPNST. Patients and Methods: The study design was a multi-institutional, open-label, Simon two-stage, phase II study of the MEK inhibitor selumetinib and mTOR inhibitor sirolimus. Patients ≥12 years with histologically confirmed MPNST received selumetinib 50 mg twice daily and sirolimus 4 mg once daily, in continuous 28-day cycles. Correlative studies evaluated patient-reported pain, immune signature in peripheral blood, and cell-free DNA (cfDNA). Results: A total of 21 heavily pretreated patients [seven females; median age, 41 years (range, 16–72); and 14 with NF1] with advanced disease enrolled at five participating sites. Clinical benefit was observed in only one of seven in stage 1 and one of 14 patients in stage 2. The median number of cycles was two (range, 1–6). Most common adverse events (AE) were grade ≤2 gastrointestinal toxicity, acneiform rash, hypertriglyceridemia, mucositis, and transaminase elevation. Unlike the preclinical model, early 18F-fluorodeoxyglucose PET scan performed during cycle 1 demonstrated partial metabolic responses in five patients (24%), but these did not correlate with objective responses after cycle 2. cfDNA was able to detect MPNST with the potential to be a biomarker of response. Conclusions: The combination was safe, with manageable and expected AEs, but did not meet study parameters for further evaluation in MPNST. Correlative studies were informative and may guide future therapeutic trials of MPNST.

Abstract Background The Joint Propagation Model (JPM)‐based CenTauR scale was recently introduced to harmonize tau‐PET quantification across different radiotracers. This study examined how CenTauR harmonization enhances the comparability of tau‐PET quantification across matched cohorts using different tracers. The evaluation focused on three key aspects: (1) comparing tau‐PET positivity rates as defined by CenTauR, (2) evaluating its diagnostic accuracy for symptomatic AD, and (3) analyzing longitudinal changes in tau‐PET rates over time. Method The JPM, developed by the CPAD‐led Tau PET Harmonization Working Group (Leuzy et al., Alzheimers Dement. 2024; Figure 1A), models relationships between anchor point subjects and head‐to‐head tau‐PET SUVR data onto the CenTauR scale, providing conversion equations for multiple tracers. JPM equations were applied to [ 18 F]flortaucipir SUVR (Meta‐temporal ROI) data from 561 cognitively impaired participants in the ADNI and OASIS‐3 studies. Using ROC analysis, we determined the CenTauR cut‐off for positivity (T+) that maximized the Youden index for discriminating between FDA‐approved positive/negative visual reads. Three separate cohorts, scanned using [ 18 F]flortaucipir (ADNI), [ 18 F]MK‐6240 (CPAS), and [ 18 F]RO‐948 (BioFINDER‐2), were matched 1:1 by age, MMSE, amyloid‐β, and clinical diagnosis. CenTauR‐based metrics were compared across these cohorts. Result A cut‐off of 18 CenTauRs was found to optimally classify [ 18 F]flortaucipir PET visual reads (Figure 1B). The matching procedure identified 1089 participants (363 per cohort). The frequency of T+ using the 18 CenTauRs cut‐off for the Meta‐Temporal ROI was highly comparable across tracers across groups, except for the Aβ‐positive cognitively unimpaired group, where variability was more pronounced due to a smaller sample size (Figure 2A). Similarly, tau‐PET discriminative accuracy for symptomatic AD vs controls remained similar across [ 18 F]flortaucipir and [ 18 F]MK‐6240 (Figure 2B). In a separate sample of 212 matched participants from ADNI ([ 18 F]flortaucipir) and AIBL ([ 18 F]MK‐6240) with baseline and 1‐year follow‐up tau‐PET scans, 1‐year change in CenTauRs was comparable (Figure 2C). An exploratory voxelwise transformation, utilizing the Meta‐Temporal conversion equation in a representative case scanned with both [ 18 F]flortaucipir and [ 18 F]MK‐6240, demonstrates the potential for voxelwise CenTauR harmonization (Figure 3). Conclusion These analyses suggest that CenTauR harmonization increases the comparability of tau‐PET data acquired with different tracers. Additional validation analyses with larger cohorts including other radiotracers ([ 18 F]PI‐2620) are underway.

Abstract Background The incidence of early onset breast cancers (BCs) has increased, paralleling rising trends in delayed childbearing. We hypothesize that a distinct postpartum BC (PPBC) subtype, identifiable by time since last birth (TSLB) and biomarker expression, contributes to this trend. Methods We applied GeoMx Digital Spatial Profiling (DSP) to measure associations between TSLB and 71 proteins in 640 BCs from women aged ≤40 years included in the Young Women’s Breast Cancer Study. We analyzed data using univariable linear regression and multivariable sliced inverse regression to account for higher order interactions among biomarkers. Results In keratin-rich segments, progesterone receptor (PR) (P = 1.00 × 10−4) and PTEN (P = 1.00 × 10−3) were associated with longer TSLB; multivariable analyses revealed positive associations for GZMB (P = 4.00 × 10−4), SMA (P = 1.00 × 10−4), and NF-1 (P = 1.00 × 10−3). In keratin-poor segments, univariable significant positive associations were found for PR (P = 2.00 × 10−4) and PTEN (P = 1.00 × 10−3), whereas CD20 (P = 3.00 × 10−4) and CTLA4 (P = 4.00 × 10−5) were negatively associated; multivariable significant associations were found for fibronectin (P = 3.00 × 10−5) and pan-Akt (P = 1.00 × 10−3). Associations persisted after adjustment for multiple comparisons and BC molecular subtypes. Associations including for PR, PTEN, and CD20 were strongest among women with the shortest TSLB. OPAL multiplex immunofluorescence assays for PR, PTEN, CD20, SMA, and CTLA4 replicated several DSP findings, particularly when stratified by subtype and with compartment matching. In TCGA, RNA species linked to proteins associated with TSLB correlated strongly with a T-cell exhaustion signature previously linked to poor prognosis among premenopausal women. Conclusion These data support PPBC as a biologically coherent phenotype defined by TSLB and biomarker profile, with potential implications for prevention and therapy.

Abstract Secondary central nervous system (CNS) large B-cell lymphoma (SCNSL) occurs in the de novo setting, as a CNS-isolated relapse, or synchronous (concomitant CNS and systemic) relapse. SCNSL is a devastating event without therapeutic consensus. Thus, we aimed to evaluate treatment outcomes in an international cohort. Progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR, estimated using competing-risk models) were reported. Prognostic factors were identified in a 6-month landmark multivariate analysis. Outcomes after thiotepa autologous stem cell transplant (ASCT) and chimeric antigen receptor (CAR) T-cell therapy (CAR-T) delivered at relapse were compared after propensity score matching (PSM). A total of 1139 patients were included in the analysis (de novo: 537; relapsed SCNSL: 602). Two-year PFS estimates were 40.4%, 43.9%, and 16.2% for de novo SCNSL, CNS-isolated relapse, and synchronous relapse, respectively. Patients with CNS-isolated relapse demonstrated low rates of systemic recurrence (24-month CIR, 6%). Thiotepa-ASCT correlated with longer survival in de novo SCNSL (PFS: hazard ratio [HR], 0.57; P = .005; and OS: HR, 0.62; P = .023) and CNS-isolated relapses (PFS: HR, 0.55; P = .002; and OS: HR, 0.39; P&lt; .0001). ASCT (thiotepa or no thiotepa) also associated with improved survival in synchronous relapses (PFS: HR, 0.57; P = .023; and OS: HR, 0.48; P = .019). Higher survival with thiotepa-ASCT than CAR-T was observed after PSM (PFS: HR, 0.45; P = .005 and OS: HR, 0.41; P = .014). These data support thiotepa-ASCT in eligible patients, particularly de novo disease and CNS-isolated relapses. CNS-isolated relapse was infrequently associated with systemic recurrence, supporting treatment regimens adopted from primary CNS lymphoma.